Scientists work on manipulating Alzheimer's gene

The gene for apolipoprotein E4, or ApoE4, confers the largest known genetic risk for Alzheimer's disease, but that's not all. People who carry the gene also do much worse if they develop multiple sclerosis, Lou Gehrig's disease, Parkinson's disease, sleep apnea and other forms of dementia. They don't recover as well from traumatic brain injury or stroke. They are more likely to develop "pump head" — a combination of memory problems and mental fogginess — if they have heart bypass surgery. People with sleep apnea, who stop breathing many times during the night, tend to develop more memory and thinking problems if they carry the gene for ApoE4.

On top of that, problems caused by ApoE4 don't wait until old age. Effects have been detected much earlier in life. A recent paper in JAMA Neurology even reported that ApoE4 babies display brain changes that could contribute to Alzheimer's disease later in life.

Why would a gene that contains instructions for assembling the ApoE4 protein, which transports fats, cholesterol and other substances around the body, cause so much trouble? And why don't the genes for the ApoE2 and ApoE3 proteins — the two other forms of the protein in humans — cause the same problems?

Robert Mahley, who has studied cholesterol and the ApoE protein for decades, says the problem lies in one tiny difference that sets ApoE4 apart from the other two variations. And he believes this difference can be corrected, which would eliminate the vulnerability to brain dysfunction that ApoE4 carriers now face.

The ApoE protein consists of 299 amino acids linked like pearls on a coil. Most of the coil folds into a large domain that resembles the palm of a hand with the four fingers held tightly together. The other domain resembles the thumb extended away from the palm.

In ApoE2 and ApoE3, the "thumb" remains comfortably apart from the "hand," according to Dr. Mahley, president emeritus of the Gladstone Institutes in San Francisco. The ApoE4 protein, however, possesses a different amino acid in one position that causes the thumb to stick to the hand. When the two domains stick together, the protein folds inappropriately, getting broken down by brain cells for recycling or elimination. The resulting fragments tend to accumulate in the cells, causing stress that contributes to their death.

Mahley and Yadong Huang, his longtime collaborator at Gladstone, believe they have a way of fixing this problem. In a paper published in 2012 they described a "structure corrector" known as PY-101 capable of preventing the thumb of the ApoE4 protein from sticking to the hand. This makes ApoE4 essentially identical to ApoE3, which carries no additional risk for Alzheimer's disease.

"We can change structure of E4 to make it E3-like, and in so doing we correct the detrimental effects ApoE4 has in mouse models," Mahley said.

Now Gladstone researchers are trying to develop a pill that will do the same in humans, and Mahley predicts human clinical trials may begin within two years. To help advance the idea the Wellcome Trust recently bestowed a $2.5 million "Seeding Drug Discovery Award" on Dr. Mahley and his colleagues, and they have formed a partnership with a drug design firm located near San Francisco to develop a structure corrector in pill form that will prevent human ApoE4 from misfolding.

"We've already proven that PY-101 gets into the brain, so we're trying to develop a formulation that's orally available," he said. "We're working that out in our mice right now."

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